Download Position Statement on vCJD Nov 2015

UK Blood Services Joint Professional Advisory Group
Position Statement
Creutzfeldt-Jakob Disease
25 May 2015
Prepared by: Originally prepared by the vCJD Working Party of the Standing Advisory
Committee on Transfusion Transmitted Infections, becoming the responsibility of the UK
Blood Services Prion Working Group in June 2010.
This document will be reviewed whenever further information becomes available.
Please continue to refer to the website for in-date versions.
Background
Creutzfeldt-Jakob disease (CJD) is one of a group of diseases called Transmissible
Spongiform Encephalopathies (TSE) or prion diseases. These diseases, in general, have
long incubation periods and are characterized by severe and irreversible damage to the
central nervous system resulting in death. The diseases are caused by prions, which differ
from conventional microorganisms such as bacteria and viruses. So far there are no
clinically effective treatments for any TSE including CJD.
Sporadic, iatrogenic and familial Creutzfeldt-Jakob disease
Sporadic CJD (sCJD), which was first described in the early 1920s, occurs worldwide and
affects around one to two persons per million per year with a median age of onset of 65
years. Patients experience a rapidly progressive dementia with death typically occurring
within six months of their first symptoms. Other forms of human prion disease have since
been described, including Kuru which was endemic in the Fore people of Papua New
Guinea in the 1950s and transmitted through cannibalistic funeral rites. There are also rare
familial forms of human prion disease due to inherited genetic abnormalities. In addition,
transmission of sCJD has occurred in the past during medical care through neurosurgical
instruments, corneal and dura mater grafts and cadaveric pituitary derived human growth
hormone and gonadotrophins. A series of epidemiological case control, look back and
surveillance studies over the last twenty years have not revealed any confirmed cases of
transmission of sCJD by blood components, plasma products, or peripheral tissues (such as
bone, skin and heart valves). However, as a precautionary measure, UK Blood Services
apply agreed UK and European exclusion criteria (in line with WHO recommendations) to
exclude anyone who could have an increased risk of iatrogenic or familial CJD from donating
blood, tissues or stem cells.
UK Blood Transfusion Services criteria for excluding blood and tissue donors who have, or
who could have, an increased risk of human prion diseases:
Obligatory:
Must not donate if:
Diagnosed with any form of CJD, or other human prion disease.
Identified at increased risk of developing CJD or another form of human
prion disease.
This includes:
o Individuals at familial risk of CJD or another form of human prion
disease (have had two or more blood relatives develop CJD or
another form of human prion disease or have been informed
following genetic counselling that they are at risk)
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UK Blood Services Joint Professional Advisory Group
Position Statement
Creutzfeldt-Jakob Disease
25 May 2015
o
Individuals who have been told that they have been put at
increased risk from surgery, transfusion or transplant of tissues or
organs.
o
Individuals who have been told that they may be at increased risk
because a recipient of blood or tissues that they have donated has
developed a human prion disease.
o
Recipients of dura mater grafts.
o
Recipients of corneal, scleral or other ocular tissue grafts.
o
Recipients of human pituitary derived extracts.
Exceptions: If the donor has had two or more blood relatives develop CJD or another form
of human prion disease and, following genetic counselling, they have been
informed that they are not at risk, accept.
This requires confirmation by a Designated Medical Officer.
Variant Creutzfeldt-Jakob Disease (vCJD)
A different form of Creutzfeldt-Jakob disease - vCJD - was first reported in 1996. Unlike
sCJD, this disease affects younger people (a median age at death of 28, range 14-75 years
old). Clinical presentation is also different. Variant CJD patients show signs of behavioural
disorder, depression and anxiety followed by problems with sensation and co-ordination
leading to progressive dementia and death over a period of on average 14 months (range 6114 months). The clinical, epidemiological, neuropathological and experimental data all point
to vCJD being caused by the same strain of prion as Bovine Spongiform Encephalopathy
(BSE). This is a different strain of prion from those seen in sCJD.
To date there have been 177 definite and probable cases of vCJD in the UK, 27 cases in
France, and 25 cases elsewhere in the world. Some of these latter cases are thought to
have acquired the disease in the UK. The other patients are thought to have been infected in
their country of origin, but possibly through eating beef of UK origin. Details on the number of
UK and world-wide cases of vCJD can be found on the National Creutzfeldt-Jakob Disease
Research and Surveillance Unit (NCJDRSU) website (www.cjd.ed.ac.uk). The eventual
number of individuals within the UK population likely to develop vCJD remains uncertain and
it is similarly uncertain how many current or past blood or tissue donors could be incubating
the disease. All cases of clinical vCJD, except three from the UK, are believed to be primary
cases resulting from eating BSE contaminated meat products. In December 2003, the first
presumed transmission of vCJD by blood transfusion was described. The transfusion
occurred in 1996; the blood donor was well at the time but went on to develop symptoms of
vCJD in 1999. The recipient was diagnosed with vCJD in 2003. A probable transmission of
vCJD prions, not leading to clinical disease, was reported in July 2004. On this occasion the
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UK Blood Services Joint Professional Advisory Group
Position Statement
Creutzfeldt-Jakob Disease
25 May 2015
patient received blood in 1999 from a donor who went on to develop symptoms of vCJD 18
months later. The recipient died of unrelated causes 5 years after the transfusion with no
evidence of neurological disease but at post-mortem was found to have evidence of
abnormal prion accumulation in the spleen and a lymph node. The second presumed bloodassociated transmission leading to clinical disease was reported in February 2006. The
patient developed symptoms about 8 years after receiving a blood transfusion from a donor
who developed symptoms of vCJD about 20 months after donating blood. A third presumed
blood-associated transmission leading to clinical disease was reported in January 2007 in a
patient who developed symptoms just over 8 years after receiving a blood transfusion from a
donor whose symptoms of vCJD appeared about 17 months after donating this blood. This
donor was also associated with one of the earlier transmissions.
A further presumed transmission of prions was described in February 2009. The patient
suffered from haemophilia and had received batches of factor VIII to which a donor who
subsequently developed vCJD had contributed plasma. The patient died of other causes but
was found at post-mortem to have evidence of prion accumulation in his spleen. Further
details are published in Peden et al. (Haemophilia 2010; 16: 296-304).
The UK Blood Services have taken a number of measures to try to reduce the risk of
transmission of vCJD by blood, plasma and tissue products:
These include:
Withdrawal and recall of any blood components, plasma derivatives, cells or tissues
obtained from any individual who later develops vCJD (announced December 1997).
Importation of plasma from countries other than the UK for fractionation to manufacture
plasma derivatives (announced May 1998, fully implemented October 1999).
Leucodepletion of all blood components (decision announced July 1998, fully
implemented Autumn 1999).
Importation of clinical Fresh Frozen Plasma (FFP) for patients born on or after 1st
January 1996, announced on 16 August 2003 and implemented by the end of June
2004. This was extended to all patients under the age of 16 by July 2005. As those born
on or after 1st January 1996 began to turn 16 from 1 January 2012, this rule reverted to
its original wording to ensure that these individuals continued to receive imported plasma
past their 16th birthday.
Exclusion of whole blood donors who state that they have received a blood component
transfusion in the UK since 1st January 1980, (April 2004). Extended to whole blood and
apheresis donors who may have received a blood component transfusion in the UK
since 1st January 1980, (August 2004) and to any donors who have been treated with
UK plasma derived intravenous immunoglobulin or have undergone plasma exchange.
This was further extended in November 2005 to transfusions anywhere in the world.
Exclusion of live bone donors who have been transfused since 1st January 1980 (July
2005).
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25 May 2015
Exclusion of blood donors whose blood has been transfused to recipients who later
developed vCJD, where blood transfusion cannot be excluded as a source of the vCJD
infection and where no infected donor has been identified (July 2005).
Promotion of appropriate use of blood and tissue products and alternatives throughout
the NHS.
Questions and Answers
How many people are currently incubating vCJD in the UK?
Estimates of the number of people likely to develop vCJD (and therefore currently incubating
the disease) continue to vary. It is also possible that some people could be "infected" with
this agent but never progress to clinical disease. Data collected by the National CJD
Research and Surveillance Unit show that vCJD mortality in the UK peaked in 2000 and has
since fallen. The observation is encouraging; however some caution should be exercised.
There is currently a discrepancy between the likely number of cases projected from the
current clinical evidence of vCJD and the number of infected people projected from
retrospective studies of tonsil and appendix samples which suggests that around 1/2,000
(range 1/1,250 to 1/3,500) healthy people in the general population could be sub-clinically
infected (http://transparency.dh.gov.uk/2012/08/13/tse-risk-assessment-july-2012/).
To date all probable and definite cases of clinical vCJD have been in people who are
methionine homozygous at codon 129 of the prion protein gene. A single UK case of
possible vCJD in a patient who was heterozygous at this genetic locus has been described.
In addition, the second of the transfusion recipients and the patient with haemophilia referred
to above, both of whom had evidence of abnormal prion protein, were heterozygous at this
locus and two of the patients positive for abnormal prion accumulation in the retrospective
study of tonsils and appendices were homozygous for valine. These observations suggest
that other genotypes may also be susceptible to infection with vCJD prions, possibly with a
lower frequency of clinical disease and/or longer incubation periods (as has been seen in
some cases of Kuru and peripherally transmitted iatrogenic CJD). In addition, further cases
could arise due to secondary human to human transmission via medical or surgical
instruments or blood, plasma, cell or tissue products, though no known such cases have
been seen.
How many UK patients have been exposed to blood components or plasma products
from donors who went on to develop vCJD and have they been informed?
Eighteen people who later developed vCJD have been traced as blood donors and gave
blood donations that were transfused to recipients. Sixty-seven recipients of blood
components from these donors have been identified of whom 14 are still alive, all of whom
have survived for at least 10 years since the blood transfusion. Their doctors have been
informed of their exposure to these products (http://www.cjd.ed.ac.uk/TMER/TMER.htm).
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25 May 2015
Eleven blood donors who later developed vCJD contributed to 25 plasma pools from which
191 plasma product batches were manufactured. The CJD Incidents Panel (since
disbanded) requested a model to help assess the level of risk of exposure to vCJD for
recipients of plasma products. This model was developed by the HPA and is now maintained
by its successor body, PHE. The model allows one to calculate a dose of each product (in
implicated or non-implicated batches) beyond which it is likely that an infection-control
threshold will be surpassed. It has been kept under regular review, and has informed patient
notification (and de-notification) exercises. Patients recognized to be at increased risk of
exposure have, where possible, been informed of their exposure to these products and
precautionary steps taken to minimize the risk of any further transmission through blood,
tissue or organ donation, or by medical or surgical instrumentation. Further information can
be
obtained
from
the
Public
Health
England
website.
https://www.gov.uk/government/collections/creutzfeldt-jakob-disease-cjd-guidance-data-andanalysis.
How many UK patients are exposed to blood components each year and have not
developed vCJD?
Estimates of numbers of transfusion recipients in hospitals supplied by NHSBT were made
from data collected from representative hospitals in 2001/2002 and published in 2009. The
figures for the 12 month period were: red cells: 433,000 recipients, FFP: 57,500, and platelet
components 41,500. Since NHSBT accounts for the majority of issued blood components in
the UK, the approximate figures for total number of UK recipients can be estimated by
uplifting these figures by 20% though it should also be noted that demand for red cells has
fallen significantly since this study was carried out. The median age of the recipients was 69
years, 64 years, and 59 years respectively. The EASTR study is following the survival of
these recipients for 10 years post-transfusion to determine the long-term survival of the
cohort, but previous studies have suggested that approximately 50% of blood components
are transfused into recipients who die within 10 years of transfusion. A proportion of
recipients in any one year may be transfused in following years, so it is not possible to give
an accurate figure for the total number of people who have been transfused in the UK since
the appearance of vCJD (1996) but the total will be many millions of people. Just ten of
these many millions have developed clinical vCJD, including the three (referred to above)
who have been linked to a donor who also later developed vCJD. In one case the
transfusion was given close to disease onset, and in two cases the donations could not be
linked to identified blood donors. In the remaining four cases all, or most of, the blood donors
could be identified, and none of the donors has developed vCJD.
Are additional donor selection criteria being applied?
Countries outwith the UK, including the USA, Canada, New Zealand, Australia, Hong Kong
and several European countries including Germany, Switzerland, Austria and Eire have
taken the precautionary step of excluding blood donors who have spent more than a defined
period living in the UK between 1980 and 1996. From 5th April 2004, whole blood donors
who know that they have received blood component transfusions in the UK on or after 1st
January 1980 have been excluded from blood donation. This measure generally resulted in
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Creutzfeldt-Jakob Disease
25 May 2015
the deferral of 3-5% of potential blood donors. From August 2004 this deferral criterion was
extended to blood donors unsure whether they had received a transfusion and to platelet
apheresis donors. From July 2005 live bone donors were also included in this deferral
criterion. Tissue donation from deceased donors transfused or possibly transfused since
1980, except in the last week of life, is not normally accepted. Because of shortages in
supply, this exclusion does not currently apply to the donation of heart valves, ocular tissue
and skin provided the donor's total transfusion exposure is limited to less than 80 units of
blood or blood components. In addition, any history of transfusion after 1980 must be
recorded and remain part of the documentation associated with the donation. Anyone who
has received UK derived coagulation factors, intravenous normal immunoglobulin or
underwent plasma exchange between 1980 and 2001 is also deferred from blood donation.
Will the UK blood services continue to use non- transfused UK donors?
At present, the majority of blood components (i.e. red cells, platelet and clinical plasma) and
peripheral tissue (bone, skin, tendon, heart valves and cells) are derived from UK donors. It
is unlikely that large quantities of blood or tissues could be sourced from non-remunerated
donors outwith the UK. Even if this were possible, it could increase the risk of exposure to
other infectious agents, would be very difficult to implement for components with short shelf
lives and could precipitate critical shortages. The issue is therefore one of a balance of risks.
The UK Blood Services import FFP, which is then methylene blue treated in the UK, from
non-UK volunteer donors for neonates and children born after 1st January 1996. The
rationale for this cut off date is that children born since 1996 are considered to have received
minimal exposure to the BSE agent because of the effectiveness of the animal feed ban
which was fully implemented from 1996 and the exclusion of animals above 30 months
entering the food chain. The importation of FFP was extended to the treatment of all
patients under 16 years of age and this was further extended to all born on or after 1st
January 1996 as they began to turn 16 on 1 January 2012. Consideration was given to
extending this to all patients, but in March 2012 the Advisory Committee on the Safety of
Blood, Tissues and Organs (SaBTO) recommended against this.
In 2008 SaBTO endorsed the recommendation by Tissue Banking sub group to import skin
for use in people born on or after 1st January 1996. This was not mandated by Department of
Health. This recommendation is currently under review by the Advisory Committee on
Dangerous Pathogens' Transmissible Spongiform Encephalopathy sub group as skin is
ranked as a low risk tissue for vCJD transmission and skin allografts are not widely used to
treat burns in children.
Is there a blood test available for vCJD?
Not at present. The types of tests that are used to screen blood and tissue donations for
viruses cannot be applied to vCJD because of the different type of infectious agent
(abnormal prion protein rather than bacteria or virus). Researchers from the MRC Prion Unit
have developed a blood test which has been demonstrated to be sensitive enough to detect
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25 May 2015
abnormal prion in the blood of some patients with clinical vCJD. However, considerable
work is required to bring a test from the research laboratory through to the clinic and it is
currently uncertain whether the test will prove sensitive enough to detect infection in the
asymptomatic incubation period of infection.
Can donors contract vCJD from giving blood or tissues?
No. Blood donations are taken through sterile, non-reusable, disposable needles and
equipment so it is not possible for anyone to contract vCJD by blood donation. The UK Blood
Services have a duty to supply hospitals with the blood components needed for patient care.
This can only be achieved with the help of blood donors and their continued support is vital.
For live tissue donation, no excess risk is involved in the operation that would not otherwise
be incurred as part of the operation itself, to treat the patient s underlying condition. In the
context of cadaveric tissue donations this risk is not applicable.
Does universal leucodepletion reduce the risk of transmission of vCJD?
Universal leucodepletion was introduced in the UK in 1999. In patients with sCJD and in
animal models where infectivity has been found in the peripheral blood, a large proportion
has been associated with the white blood cells. Recently published animal data show that
leucodepletion removes a proportion (about 50%) of prion infectivity, but is unlikely, by itself,
to remove all infectivity. No instances of transfusion-transmission of vCJD are known to have
occurred since leucodepletion was introduced.
Are there any other component processing steps which could reduce the risk of
transmission of vCJD by blood or tissues?
The UK Blood Services supply platelets either by apheresis (i.e. from a single donor) or from
pools of 4 donors. Pooled platelets are being suspended in platelet additive solution to
remove most of the plasma, which is considered to reduce vCJD risk. No other component
processing steps have currently been demonstrated conclusively to reduce the risk of
transmission of vCJD.
For tissues, the donations are not pooled to reduced donor exposure. Steps to eliminate
cross contamination during retrieval and processing are followed to minimise risk of
transmission. More information is given below.
Are plasma derivatives likely to be infectious?
Since October 1999, all plasma products including Factor VIII and Factor IX,
immunoglobulins and albumin have been derived from non-UK donors. The majority of
clotting factors now used in the UK are recombinant products which pose no risk of vCJD
infection. Therefore, there should be minimal risk to patients now receiving plasma products
provided donors are from countries with a known low risk for BSE. The risk to patients who
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25 May 2015
received plasma products before October 1999 is uncertain, but it does now appear that a
case of transmission of infection to a patient with haemophilia has occurred, though the
patient himself did not develop clinical disease. The UK Blood Services have engaged in
research on the ability of the plasma fractionation processes to remove prions. These
studies involved the experimental addition of prion-infected material to blood and showed
that there are steps during each manufacturing process which remove prions, though it
remains unclear how closely these reflect the way in which the natural infective agent
behaves. Similar studies have been performed by other organisations with similar results.
The starting level of infection in plasma from UK donors remains unknown. The risk from
most UK derived plasma products is likely therefore to have been low, but it cannot be
assumed that the risk was zero.
Are cell or tissue products likely to be infectious?
The Standing Advisory Committee on Tissues and Cellular Therapy Products undertook a
formal review together with the Health Protection Analytical Team to consider the risks of
transmission of vCJD by cells and tissues including new safety issues raised through in vitro
propagation of cells.
Some specific initiatives have also been considered and / or implemented for improvement
in the safety of tissues within the UK Blood Services to try to reduce the risk of transmission
of vCJD by bone and tissue transplantation. These include:
Improved washing and blood removal techniques for processed sterilized bone
grafts.
The use of disposable instruments for some types of tissue retrieval and processing.
Improvement in decontamination procedures prior to sterilization of instruments.
Batching of retrieval and processing of instruments to allow for the tracking of their
use.
Dura mater grafts are not provided
Should UK patients continue to accept blood and tissue products?
Blood, plasma, cell and tissue products should only be given when they are essential to the
quality of life, health or survival of the patient, and where there is patient consent. In these
circumstances the benefits are carefully weighed against other transmission risks including
vCJD. In some circumstances alternatives are available which could reduce the exposure to
blood or tissue products. UK Blood Services clinicians continue to work with colleagues
throughout the National Health Service in establishing and implementing guidelines for the
appropriate use of blood and tissues. It is a priority for the UK Chief Medical Officers and the
medical community in the UK to ensure that patients are treated with blood or tissue
products only when there is real clinical need. SaBTO recommends that patients be offered
the opportunity to give informed consent to blood transfusion whenever practicable and a
series of information leaflets are available explaining the potential benefits and risks
including those relating to vCJD.
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Position Statement
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25 May 2015
What is being done to ensure that blood and tissues are used only when there is a good
clinical indication?
On the advice of the UK Chief Medical Officers, national programmes for good transfusion
practice have been established, supporting the work of local Hospital Transfusion
Committees. Transfusion practitioners in hospitals carry out a role. which includes training
staff in safe blood administration (including detailed documentation), assisting with clinical
audit, the development and implementation of evidence based clinical guidelines for the use
of blood, and assisting with the investigation and reporting of adverse events to the Serious
Hazards of Transfusion reporting scheme (SHOT). There is increasing use in the NHS of
techniques that can, for some patients, reduce the need for transfusion of donor blood or
avoid it all together. Among these are: the use of regional and hypotensive anaesthetic
techniques, good temperature control in the perioperative period, salvage and reinfusion of
red blood cells lost during surgery and the use of antifibrinolytic agents. However,
transfusion may be unavoidable and life saving for patients who suffer massive blood loss
and, for those undergoing chemotherapy for leukaemia or being treated for cancer, there
may be no alternative to the use of donor blood components during periods when the bone
marrow is not functioning normally.
Tissue usage is much more restricted than that of blood and in most instances tissues are
used when there is no better alternative. Notwithstanding, there are initiatives on auditing
usage of particular tissues in specific circumstances to encourage and facilitate best
practice.
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